In general, in normal bone metabolism, bone resorption by osteoclasts is balanced with bone formation by osteoblasts to maintain homeostasis. It is thought that an imbalance between the bone resorption and the bone formation causes bone metabolic diseases. Bones retain about 99% of the total calcium in a living body and play an important role in maintaining a constant blood calcium concentration by bone formation and bone resorption. If osteoclasts, which are mainly responsible for bone resorption, are abnormally formed or activated, bone resorption is accelerated to increase blood calcium concentration, and thereby bone metabolic diseases, such as hypercalcemia, are caused.
Conventionally, for bone metabolic diseases, hormone replacement therapy using estrogen or the like has been conducted or a therapeutic agent such as a bisphosphonate or a calcitonin that suppresses osteoclast activity has been administered (refer to Non-Patent Document 1). However, none of these existing agents can be satisfactory for essentially treating hypercalcemia or bone metabolic diseases, and therefore development of agents having high therapeutic efficacy is desired.
The following substituted propanamide derivatives are known hitherto.
(1) Patent Document 1 discloses phenylalanine derivatives shown in Table 1 having an analgesic effect and a vasodilating effect and are expected to have therapeutic effects on, for example, cerebral palsy syndromes. However, the document does not mention a bone resorption-suppressing activity at all (refer to Patent Document 1).
TABLE 1(a) No.R1aR2aR3a 1H(CH2)3CH3  2HH(CH2)2OH 3HOH(CH2)2CH3 4HOH(CH2)3CH3 5HOH(CH2)5CH3 6HOCOC6H5(CH2)2CH3 7HOCOC6H5(CH2)3CH3 8HOCOC6H5(CH2)5CH3  9CH3(CH2)3CH3 10CH3OH(CH2)3CH311CH3OH(CH2)5CH312CH3OCOC6H5(CH2)3CH313CH3OCOC6H5(CH2)5CH3 14Cl(CH2)3CH3 15Cl(CH2)3CH3 16Cl(CH2)3CH3 17ClOH(CH2)3CH318ClOCO(p-Cl—C6H5)(CH2)3CH3
(2) Patent Document 2 discloses phenylalanine derivatives shown in Table 2 having a cathepsin B inhibitory activity, but does not mention a bone resorption-suppressing activity at all (refer to Patent Document 2).
TABLE 2(b) No.R1bR2bR1b + R2bR3bR4bR5b 1HHI4-(2-pyridin-4-yl-amino-thiazol-4-Hyl)phenyl 2HHI(4-morpholin-4-yl)phenylH 3HHImorpholin-4-ylH 4cyclopropylI(4-morpholin-4-yl)phenylH 5HHI(4-morpholin-4-yl)phenylCH3 6HHI4-[2-(4-methylpiperazin-1-yl)-thiazol-4-Hyl]phenyl 7HHCH3(4-morpholin-4-yl)phenylH 8HHCH2CH3(4-morpholin-4-yl)phenylH
(3) Patent Document 3 discloses phenylalanine derivatives shown in Table 3 having a cathepsin S inhibitory activity, but does not mention a bone resorption-suppressing activity at all (refer to Patent Document 3).
TABLE 3(c) No.(R1c)m(R2c)n 13,4-dichloro3-methyl 2H3-bromo 32-tolyloxy3-methyl 43-(2-methylthiazol-4-yl)H 53-cyanoH 64-methyl3-methyl 73-methyl4-(4-dimethylaminophenyl) 82,4,5-trimethylH 93-bromo-4-methylH104-methoxy-3,5-dimethylH114-benzoyloxy-3,5-dimethylH123,5-dichloro3-methyl132-chloro-3-methylH142,3-dimethyl3-methyl153,5-dimethyl3-methyl163-chloro3-methyl173-methyl4-methoxy183-methyl4-phenoxy193-methyl4-(4-chlorophenoxy)203-methyl4-(2-methoxypyridin-5-yl)213-methyl4-(2,4-dimethoxypyridin-5-yl)223-methyl4-(3-acetylphenyl)233-methyl4-(4-hydroxyphenyl)243-methyl4-(2-acetylphenyl)253-methyl4-(2,5-dichlorophenyl)263-methyl4-(2,4-dimethoxyphenyl)273-methyl4-(3-hydroxymethylphenyl)283-methyl4-(5-fluoro-2-methylphenyl)293-methyl4-(4-hydroxymethylphenyl)303-methyl4-(3,4-dimethoxyphenyl)313-methyl4-(3-aminophenyl)323-methyl4-(2,3-dimethoxyphenyl)333-methyl4-(4-chlorophenyl)343-methyl4-(pyridin-4-yl)353-methyl4-(4-cyanophenyl)363-methyl4-(thiophen-3-yl)373-methyl4-(pyridin-3-yl)383-methyl4-(3-nitrophenyl)393-methyl4-(2-nitrophenyl)403-methyl4-phenyl413-methyl4-(3-methylphenoxy)423-methyl4-t-butyl433-methyl4-trifluoromethyl443-methyl3-trifluoromethyl453-methyl4-benzyloxy463-methyl4-fluoro473-methyl4-nitro483-methyl4-chloro493-methyl4-bromo503-methyl4-cyano513-methyl2-trifluoromethyl523-methyl3-methyl533-methyl3,4-difluoro543-methyl3-fluoro553-methyl4-methyl563-methyl4-acetamido573-methyl3,4-dichloro583-methyl3,5-difluoro593-methyl3,5-dichloro603-methyl4-hydroxy613-methyl4-t-butoxy623-methyl4-iodo63H3-methoxy    [Patent Document 1] U.S. Pat. No. 4,004,008    [Patent Document 2] International Publication No. WO 2004/026851    [Patent Document 3] International Publication No. WO 2004/084842    [Non-Patent Document 1] Mohammad M. Iqbal, et al., Missouri Medicine, 2002, vol. 99, p. 19.